CN109096134A - A kind of preparation method of equal amido phenenyl acid methyl esters - Google Patents
A kind of preparation method of equal amido phenenyl acid methyl esters Download PDFInfo
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- CN109096134A CN109096134A CN201811195038.3A CN201811195038A CN109096134A CN 109096134 A CN109096134 A CN 109096134A CN 201811195038 A CN201811195038 A CN 201811195038A CN 109096134 A CN109096134 A CN 109096134A
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- methyl esters
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- acid methyl
- acid
- paranitrophenylacetic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The embodiment of the invention provides a kind of preparation methods of equal amido phenenyl acid methyl esters, are related to pharmaceutical synthesis field, use benzene acetonitrile as starting material, and successively by nitrification, hydrolysis, esterification, reduction, high yield has obtained equal amido phenenyl acid methyl esters.The route of the preparation method is reasonable, easy to operate, not high to equipment requirement, and raw material sources are extensive, is appropriate for large-scale industrial production.
Description
Technical field
The present invention relates to pharmaceutical synthesis fields, in particular to a kind of preparation method of equal amido phenenyl acid methyl esters.
Background technique
Equal amido phenenyl acid methyl esters is that a kind of intermediate that can be used for preparing anti-AIDS drug is used in the prior art
Prepare equal amido phenenyl acid methyl esters synthetic method be not suitable for carry out large-scale industrial production, caused by direct result just
It is that the price of commercially available equal amido phenenyl acid methyl esters is generally higher, and often in state out of stock in spite of rising price.It develops a kind of simple
Convenient, the new synthesis process for being able to carry out large-scale production is very necessary.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation methods of equal amido phenenyl acid methyl esters, and route is reasonable, operation letter
Single, not high to equipment requirement, raw material sources are extensive, are appropriate for large-scale industrial production.
The embodiment of the present invention is achieved in that
A kind of preparation method of equal amido phenenyl acid methyl esters comprising:
Benzene acetonitrile is nitrified, para orientation nitration is obtained；
Esterification is carried out with methanol after para orientation nitration is hydrolyzed, obtains paranitrophenylacetic acid methyl esters；
Paranitrophenylacetic acid methyl esters is restored, equal amido phenenyl acid methyl esters is obtained.
The beneficial effect of the embodiment of the present invention is:
The embodiment of the invention provides a kind of preparation methods of equal amido phenenyl acid methyl esters, use benzene acetonitrile as starting
Raw material, successively by nitrification, hydrolysis, esterification, reduction and etc., high yield has obtained equal amido phenenyl acid methyl esters.The preparation
The route of method is reasonable, easy to operate, not high to equipment requirement, and raw material sources are extensive, and it is raw to be appropriate for large-scale industrialization
It produces.
Specific embodiment
It in order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below will be in the embodiment of the present invention
Technical solution be clearly and completely described.The person that is not specified actual conditions in embodiment, according to normal conditions or manufacturer builds
The condition of view carries out.Reagents or instruments used without specified manufacturer is the conventional production that can be obtained by commercially available purchase
Product.
A kind of preparation method of equal amido phenenyl acid methyl esters of the embodiment of the present invention is specifically described below.
The embodiment of the invention provides a kind of preparation methods of equal amido phenenyl acid methyl esters comprising:
S1. benzene acetonitrile is nitrified, obtains para orientation nitration.
Its chemical equation is
Further, to benzene acetonitrile carry out nitrification be in the mixed solution for be added to benzene acetonitrile the concentrated sulfuric acid and concentrated nitric acid into
Row reaction, reaction temperature are 0~10 DEG C, and the reaction time is 3~10h.
In practical operation, first carry out concentrated nitric acid and the concentrated sulfuric acid to be mixed and made into mixed solution, in order to prevent mixed process
Middle overheat can be carried out in such a way that the concentrated sulfuric acid to be added dropwise to concentrated nitric acid, and be controlled temperature 0~10 using ice-water bath
℃。
Further, in the reaction, the mass ratio of benzene acetonitrile, the concentrated sulfuric acid and concentrated nitric acid is 1:5~5.5:4~4.5.?
It is reacted under aforementioned proportion, high income preferable to the nitrification effect of benzene acetonitrile, more can exclusively obtain contraposition nitro and take
The nitration product in generation.
Meanwhile it is excessively violent in order to avoid reacting, benzene acetonitrile can be added to concentrated nitric acid and dense sulphur by way of dropwise addition
Acid mixed solution in, drop rate control in 10~20g/h, after being added dropwise, at 0~10 DEG C continue insulation reaction 3~
5h。
After the reaction was completed, reaction solution is poured into ice water, drain, wash, filter after obtain crude product.Crude product returns in methyl alcohol
After flowing 30~60min, filters and dry, para orientation nitration can be obtained.
Further, a kind of preparation method of equal amido phenenyl acid methyl esters provided by the embodiment of the present invention, further includes:
S2. esterification is carried out with methanol after para orientation nitration being hydrolyzed, obtains paranitrophenylacetic acid methyl esters.
Specifically comprising:
S2-1. first para orientation nitration is hydrolyzed in acid condition, obtains paranitrophenylacetic acid, chemically reacted
Formula is
Further, para orientation nitration is hydrolyzed to be by para orientation nitration and concentration be 40%~60% it is dilute
Sulfuric acid mixing, and 10~15h of temperature rising reflux.
After the reaction was completed, it is down to room temperature, reaction solution is poured into ice water, is filtered, is washed to after neutrality and drains, dries, i.e.,
Paranitrophenylacetic acid can be obtained.
Wherein, the mass ratio of para orientation nitration and dilute sulfuric acid is 1:5~6.Under the above-described reaction conditions, for cyano
Hydrolysis is more thorough, conducive to paranitrophenylacetic acid is obtained in high yield.
S2-2. the paranitrophenylacetic acid and methanol hydrolysis obtained carries out esterification, obtains paranitrophenylacetic acid methyl esters,
Its chemical equation is
Optionally, above-mentioned esterification is carried out under the catalysis of the concentrated sulfuric acid, and reaction process needs to be warming up to reflux shape
State, when reaction a length of 12~18h.
After fully reacting, reaction solution is poured into 10%~20% sodium carbonate liquor of concentration and is neutralized, is washed after suction filtration
Until it is neutral, then drained, dried, paranitrophenylacetic acid methyl esters can be obtained.
Wherein, the mass ratio of paranitrophenylacetic acid, methanol and the concentrated sulfuric acid is 1:1.2~1.8:0.1~0.2.In above-mentioned ratio
It is reacted under example, it can be ensured that paranitrophenylacetic acid fully reacting obtains paranitrophenylacetic acid methyl esters in high yield.
Further, a kind of preparation method of equal amido phenenyl acid methyl esters provided by the embodiment of the present invention, further includes:
S3. paranitrophenylacetic acid methyl esters is restored, obtains equal amido phenenyl acid methyl esters.
Its chemical equation is
Further, the reduction of paranitrophenylacetic acid methyl esters is to mix paranitrophenylacetic acid methyl esters with iron powder, in dense salt
Under the catalysis of acid, triethyl benzyl ammonia chloride and ammonium chloride, 7~15h of temperature rising reflux.Iron powder carries out reduction to nitro and forms ammonia
Base obtains equal amido phenenyl acid methyl esters.
The reaction can be first by ammonium chloride, triethylbenzyl ammonium chloride and iron in practical operation using heterogeneous system
Powder is soluble in water, and concentrated hydrochloric acid is added, and is warming up to 1~2h of reflux activation.P-nitrophenyl second is added dropwise into the reaction solution after activation again
The toluene solution (concentration 20%~30%) of sour methyl esters, after being added dropwise, 5~7h of reflux heat preservation is reacted.
After the reaction was completed, it is down to room temperature suction filtration, filter residue is washed with toluene, merges mother liquor.Mother liquor liquid separation collected organic layer leads to
Vacuum distillation is crossed, 130~134 DEG C/5mmHg fraction is collected, obtains equal amido phenenyl acid methyl esters.
Optionally, the mass ratio of paranitrophenylacetic acid methyl esters, iron powder and concentrated hydrochloric acid is 1:0.9~1.2:0.5~0.7.?
It is reacted under aforementioned proportion, can guarantee that paranitrophenylacetic acid methyl esters reacts completely, improve the yield of product.
A kind of preparation method of equal amido phenenyl acid methyl esters provided in an embodiment of the present invention uses benzene acetonitrile as starting
Raw material, successively by nitrification, hydrolysis, esterification, reduction and etc., obtained equal amido phenenyl acid methyl esters, total recovery reaches 65%
More than.The route of the preparation method is reasonable, easy to operate, not high to equipment requirement, and raw material sources are extensive, can be effectively controlled production
Cost, and its high income, product quality is preferable, has better meet the market demand.It is very suitable to carry out large-scale industry
Metaplasia produces.
Feature and performance of the invention are described in further detail with reference to embodiments.
Embodiment 1
Present embodiments provide a kind of preparation method of para orientation nitration comprising following steps:
S1. the concentrated nitric acid that 413g concentration is 64% is added into the four-hole bottle of 1000mL, is cooled to 5 DEG C, and to four-hole bottle
The interior concentrated sulfuric acid that 506g concentration is added dropwise and is 98%, 3h are dripped off.
S2. it is cooled to 0 DEG C, in 0~10 DEG C of dropwise addition 100g benzene acetonitrile, 7h is added dropwise.After being added dropwise to complete, 0~10 is kept
DEG C the reaction was continued 3h.
S3. above-mentioned reaction solution is poured into the 2000mL beaker equipped with 800g ice water, stirs, drains, then wash, filtered,
Obtain crude product about 200g.
S4. above-mentioned crude product is added in four-hole bottle of the 1000mL with reflux condensing tube, 450g methanol, temperature rising reflux is added
30min is cooled to room temperature, and is filtered and is dried, and para orientation nitration (110g, yield 80%, mp:114.5~116 DEG C) is obtained.
Embodiment 2
Present embodiments provide a kind of preparation method of paranitrophenylacetic acid comprising following steps:
S1. 527g water is added into four-hole bottle of the 1000mL with reflux condensing tube, the 559g concentrated sulfuric acid is slowly added dropwise, is configured to
The dilute sulfuric acid that concentration is about 50%.
S2. 190g para orientation nitration is added into above-mentioned dilute sulfuric acid, temperature rising reflux reacts 10h.
S3. above-mentioned reaction solution is poured into the 2000mL beaker equipped with 800g ice water, is sufficiently stirred evenly, filtered, be washed to and wash
Water is in neutrality, and is drained, and drying obtains paranitrophenylacetic acid (209g, yield 99%, mp:150~151 DEG C).
Embodiment 3
Present embodiments provide a kind of preparation method of paranitrophenylacetic acid methyl esters comprising following steps:
S1. 626g methanol is added into four-hole bottle of the 1000mL with reflux condensing tube, the 67.5g concentrated sulfuric acid is slowly added dropwise, with
And 414g paranitrophenylacetic acid, it is warming up to back flow reaction 12h.
S2. above-mentioned reaction solution is cooled to room temperature, and pours into the 2000mL beaker equipped with 72.2g sodium carbonate Yu 672g water
In, it drains, is washed to wash water and is in neutrality, drain and obtain paranitrophenylacetic acid methyl esters (434g, yield 97%, mp:53 after drying
~54 DEG C).
Embodiment 4
Present embodiments provide a kind of preparation method of equal amido phenenyl acid methyl esters comprising following steps:
S1. 570g water, 5g ammonium chloride, 2g triethylbenzyl chlorination are added into four-hole bottle of the 1000mL with reflux condensing tube
Amine and 82.5g iron powder, starting stirring, are added 45g concentrated hydrochloric acid, are warming up to reflux activation 1h.
S2. into the mixed liquor after above-mentioned activation, dropwise addition is configured to by 260g toluene and 87.5g paranitrophenylacetic acid methyl esters
Solution, 7h is dripped off, after being added dropwise, continue back flow reaction 5h.
S3. it is filtered after above-mentioned reaction solution being cooled to room temperature, filter residue carries out washing filtering with 80g toluene, merges mother liquor and adds
Entering the liquid separation into 2000mL separatory funnel, removes water layer, collected organic layer, first rushing pump decompression with water, to steam toluene recovery stand-by,
Product is steamed with high-vacuum pump again.In distillation process, 130~134 DEG C/5mmHg fraction, as equal amido phenenyl acid methyl esters are collected
(62g, purity 99.1%, yield 90%), in terms of starting material benzene acetonitrile, the total recovery of equal amido phenenyl acid methyl esters is 69%.
In conclusion using benzene second the embodiment of the invention provides a kind of preparation method of equal amido phenenyl acid methyl esters
Nitrile is as starting material, and successively by nitrification, hydrolysis, esterification, reduction, high yield has obtained equal amido phenenyl acid first
Ester.The route of the preparation method is reasonable, easy to operate, not high to equipment requirement, and raw material sources are extensive, is appropriate for large-scale
Industrialized production.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of preparation method of equal amido phenenyl acid methyl esters characterized by comprising
Benzene acetonitrile is nitrified, para orientation nitration is obtained；
Esterification will be carried out with methanol after para orientation nitration hydrolysis, obtains paranitrophenylacetic acid methyl esters；
The paranitrophenylacetic acid methyl esters is restored, equal amido phenenyl acid methyl esters is obtained.
2. preparation method according to claim 1, which is characterized in that carrying out nitrification to the benzene acetonitrile is by the benzene second
Nitrile, which is added in the mixed solution of the concentrated sulfuric acid and concentrated nitric acid, to be reacted, reaction temperature be 0~10 DEG C, the reaction time be 3~
10h。
3. preparation method according to claim 2, which is characterized in that the quality of the benzene acetonitrile, the concentrated sulfuric acid and concentrated nitric acid
Than for 1:5~5.5:4~4.5.
4. preparation method according to claim 1, which is characterized in that it is by institute that the para orientation nitration, which is hydrolyzed,
It states para orientation nitration to mix with dilute sulfuric acid, and 10~15h of temperature rising reflux, obtains paranitrophenylacetic acid；Wherein, dilute sulfuric acid is dense
Degree is 40%~60%.
5. the preparation method according to claim 4, which is characterized in that the mass ratio of the para orientation nitration and dilute sulfuric acid
For 1:5~6.
6. the preparation method according to claim 4, which is characterized in that the paranitrophenylacetic acid is mixed with methanol,
Under the catalysis of the concentrated sulfuric acid, 12~18h of temperature rising reflux carries out esterification, obtains the paranitrophenylacetic acid methyl esters.
7. preparation method according to claim 6, which is characterized in that the paranitrophenylacetic acid, methanol and the concentrated sulfuric acid
Mass ratio is 1:1.2~1.8:0.1~0.2.
8. preparation method according to claim 1, which is characterized in that the reduction to the paranitrophenylacetic acid methyl esters be by
The paranitrophenylacetic acid methyl esters is mixed with iron powder, under the catalysis of concentrated hydrochloric acid, triethyl benzyl ammonia chloride and ammonium chloride, heating
Flow back 7~15h.
9. preparation method according to claim 8, which is characterized in that the paranitrophenylacetic acid methyl esters, iron powder and dense salt
The mass ratio of acid is 1:0.9~1.2:0.5~0.7.
10. preparation method according to claim 9, which is characterized in that restore the paranitrophenylacetic acid methyl esters
After filter, filtrate liquid separation collect organic phase；The organic phase is evaporated under reduced pressure, 130~134 DEG C/5mmHg fraction is collected,
Obtain the equal amido phenenyl acid methyl esters.
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Cited By (1)
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| CN113912489A (en) * | 2021-11-23 | 2022-01-11 | 宁夏常晟药业有限公司 | Synthetic method of methyl phenylacetate |
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| CN103408501A (en) * | 2013-08-14 | 2013-11-27 | 合肥医工医药有限公司 | Benzyl pyrimidine derivatives, and preparation method and medical application thereof |
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Application publication date: 20181228 |